Alzheimer disease is the leading cause of dementia and the 6th commonest cause of death in the United States. Familial Alzheimer disease (fAD) is associated with mutations in the genes encoding amyloid precursor protein (APP), presenilin 1 (PS1) and presenilin 2 (PS2). PS1 and PS2 are the enzymatic component of the g-secretase complex that cleaves APP to release the A42 peptide. Despite more that 15 years of study, a clear understanding of how mutations in PS1 and PS2 cause PS dysfunction and subsequent neurodegeneration has not emerged. The amyloid hypothesis suggests that Alzheimer disease (AD) develops as a toxic gain of presenilin function leading to excessive production of A42. However, therapeutic interventions directed at decreasing A42 in AD have not yet yielded clinically practical treatments. It is becoming clear that additional mechanisms including neuroinflammation contribute to the development or progression of AD and thus may be additional potential avenues for therapy design. While AD associated PS mutations can lead to a higher A42:40 ratio in vitro, many concomitantly lead to impaired 3-secretase cleavage of substrates with well described roles in inflammation, development and differentiation. Therefore, PS mutations may have damaging consequences to basic cellular pathways. We have recently described an early onset AD patient who carries a novel PS2 premature termination codon mutation leading to decreased PS2 protein, supporting the hypothesis that loss of PS2 function can contribute to neurodegeneration. Conditional PS1/PS2 knockout mice recapitulate many features of AD including neurodegeneration, upregulation of inflammatory genes, and increased numbers of microglia, the primary innate immune effector cells in the CNS. We found in both PS2 shRNA stably expressing microglia cell lines and primary microglia isolated from PS2 knockout mice that PS2 deficiency is associated with an exaggerated release of pro- inflammatory cytokines. These results were reproducible in microglia exposed to a pharmacological 3- secretase inhibitor suggesting that PS2 modulates microglia through its enzymatic activity. We have also determined that one possible mechanism by which PS2 impacts microglia behavior is through regulation of two innate immunity associated microRNAs, miR146a and miR146b. PS2 deficiency is associated with decreased levels of miR146a/b and increased levels of the miR146a target, the inflammatory signaling molecule, IRAK-1. Taken together, these observations support the hypothesis that decreased PS2 function may contribute to neurodegeneration in AD by enhancing microglial neuroinflammation. In this proposal we will 1) evaluate the central nervous system inflammatory profile of patients with PS2 mutation associated familial and sporadic AD 2) investigate the regulation of miR146a/b by PS2 and 3) study the neuroinflammatory characteristics of a transgenic mouse model conditionally expressing the most common PS2 fAD associated mutation.